Variability in plasma rifampicin concentrations and role of SLCO1B1, ABCB1, AADAC2 and CES2 genotypes in Ethiopian patients with tuberculosis

Abstract

Background

Rifampicin, a key drug against tuberculosis (TB), displays wide between-patient pharmacokinetics variability and concentration-dependent antimicrobial effect. We investigated variability in plasma rifampicin concentrations and the role of SLCO1B1, ABCB1, arylacetamide deacetylase (AADAC) and carboxylesterase 2 (CES-2) genotypes in Ethiopian patients with TB.

Methods

We enrolled adult patients with newly diagnosed TB (n = 119) who had received 2 weeks of rifampicin-based anti-TB therapy. Venous blood samples were obtained at three time points post-dose. Genotypes for SLCO1B1 (c.388A > G, c.521T > C), ABCB1 (c.3435C > T, c.4036A > G), AADACc.841G > A and CES-2 (c.269-965A > G) were determined. Rifampicin plasma concentration was quantified using LC-MS/MS. Predictors of rifampicin C_max and AUC_0–7 h were analysed.

Results

The median rifampicin C_max and AUC_0–7 were 6.76 µg/mL (IQR 5.37–8.48) and 17.05 µg·h/mL (IQR 13.87–22.26), respectively. Only 30.3% of patients achieved the therapeutic efficacy threshold (C_max>8 µg/mL). The allele frequency for SLCO1B1*1B (c.388A > G), SLCO1B1*5 (c.521T > C), ABCB1 c.3435C > T, ABCB1c.4036A > G, AADAC c.841G > A and CES-2 c.269-965A > G were 2.2%, 20.2%, 24.4%, 14.6%, 86.1% and 30.6%, respectively. Sex, rifampicin dose and ABCB1c.4036A > G, genotypes were significant predictors of rifampicin C_max and AUC_0–7. AADACc.841G > A genotypes were significant predictors of rifampicin C_max. There was no significant influence of SLCO1B1 (c.388A > G, c.521T > C), ABCB1c.3435C > T and CES-2 c.269-965A > G on rifampicin plasma exposure variability.

Conclusions

Subtherapeutic rifampicin plasma concentrations occurred in two-thirds of Ethiopian TB patients. Rifampicin exposure varied with sex, dose and genotypes. AADACc.841G/G and ABCB1c.4036A/A genotypes and male patients are at higher risk of lower rifampicin plasma exposure. The impact on TB treatment outcomes and whether high-dose rifampicin is required to improve therapeutic efficacy requires further investigation.

Keywords:

• Rifampicin
• pharmacokinetics
• pharmacogenetics
• SLCO1B1
• ABCB1
• AADAC
• CES-2
• genotype
• Ethiopia
• tuberculosis

Acknowledgments

The authors thank all study participants and staff of health centres involved in patient recruitment and sample collection. A.Z. acknowledges support from the EU-EDCTP-funded PANDORA-ID-NET program. A.Z. is in receipt of a UK National Institute for Health Research Senior Investigator Award.

Disclosure statement

The authors declare that there is no conflict of interest.

Transparency declarations

None to declare.

Additional information

Funding

This study was supported by the Fogarty International Centre and the National Institute of Allergy and Infectious Disease of the National Institute of Health [Award No. D43 TW009127], Centre of Innovative Drug Development and Therapeutic Trial for Africa (CDT-Africa), Addis Ababa University, and The European & Developing Countries Clinical Trials Partnership (EDCTP2) [Grant Nos. CSA2016S-1618 and RIA2017MC-2009]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.